P. Morgan-Capner

A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines

We describe a new method for active post-marketing surveillance of vaccine safety based on patient records. We studied the association between diphtheria/tetanus/pertussis (DTP) vaccination and febrile convulsion, and between measles/mumps/rubella (MMR) vaccination and febrile convulsion and idiopathic thrombocytopenic purpura (ITP) in five district health authorities in England by linking vaccination records with computerised hospital admission records. We found an increased relative incidence for convulsions 0-3 days after DTP vaccination. The effect was limited to the third dose of vaccine for which the attributable risk (all ages) was 1 in 12,500 doses. Completion of vaccination by 4 months instead of 10 months after the change in the UK to an accelerated immunisation schedule may have resulted in a 4-fold decrease in febrile convulsions attributable to DTP vaccine. 67% of admissions for a convulsion 6-11 days after MMR vaccination were attributable to the measles component of the vaccine (risk 1 in 3000 doses). An excess of admissions for a convulsion 15-35 days after MMR vaccination was found only for vaccines containing the Urabe mumps strain (1 in 2600 Urabe doses). There was a causal association between MMR vaccination and ITP resulting in admission 15-35 days subsequently; there was no evidence of a mumps strain-specific effect. The estimated absolute risk of 1 in 24,000 doses was 5 times that calculated from cases passively reported by clinicians. This finding emphasises the need for active surveillance of adverse events. The record linkage method that we used is an effective way to identify vaccine-attributable adverse events.

Fetal infection after maternal reinfection with rubella: criteria for defining reinfection.

Five cases of asymptomatic maternal reinfection with rubella are described that occurred in England and Wales during 1985-8 and resulted in intrauterine infection. The criteria for diagnosing reinfection are described. In four cases the rubella contact was with the womans own children. Two women had therapeutic abortions, rubella virus being recovered from the products of conception, and three were delivered of infants with congenitally acquired disease. Though the risks associated with maternal reinfection with rubella are very small and being measured in a prospective study, it is hoped that the recently introduced augmented programme of rubella vaccination will reduce rubella in the community and therefore this small risk still further.

Predicting the impact of measles vaccination in England and Wales: model validation and analysis of policy options.

Measles incidence in England and Wales has fallen to an all-time low. Attention is now focused on preventing local outbreaks, and, in the long run, on the elimination of indigenous measles. A realistic age-structured (RAS) mathematical model of measles transmission is used to reconstruct the impact of measles vaccination in England and Wales from 1968 to the present and to evaluate the merits of future policy options. In general, the predictions of the model show good agreement with long-term age stratified case reports and seroprevalence surveys. The model underestimates the proportion of cases that are notified in 0-2-year-old children. However, recent work suggests a high degree of misdiagnosis in this age group. Projections on the basis of the existing vaccination strategy in the UK suggest that the present level of measles vaccine coverage will be insufficient to eliminate small seasonal outbreaks of measles. This result is, however, sensitive to the assumed level of vaccine efficacy. Explorations of a variety of changes to current vaccination strategy favour a 2-dose schedule with the second dose administered at age 4 years irrespective of vaccination history. A vaccination campaign in school-age children, to reduce deficits in herd immunity, would accelerate progress towards measles elimination.

Surveillance of antibody to measles, mumps, and rubella by age.

Before the introduction of measles, mumps, and rubella vaccine a survey was carried out to measure antibody prevalence to the three viruses by age. A total of 8716 samples of serum collected by five public health laboratories in different parts of England during 1986-7 were tested. Despite the current measles vaccination programme 60% of children aged 1-2 years did not have measles antibody and over 80% did not have antibodies to mumps and rubella. In the 3-4 year age group 17% of the children were susceptible to measles, 55% to mumps, and 73% to rubella. The results suggest that vaccinating children early in the second year of life will be necessary to eliminate the three diseases. The survey provides baseline data for continuing surveillance of the immediate and long term effects of the new vaccination strategy.

Antibodies to measles, mumps and rubella in UK children 4 years after vaccination with different MMR vaccines

Persistence of antibodies 4 years after vaccination with measles, mumps and rubella (MMR) vaccine from three different manufacturers was compared in 475 children who received a single injection of vaccine when aged 12-18 months. Antibodies to measles and mumps were measured using a plaque reduction neutralisation assay; rubella antibodies were measured by radial haemolysis and latex agglutination. Children given MMR vaccine containing the Urabe mumps strain were less likely to be antibody negative than those given the Jeryl Lynn mumps strain (39/266, 15% vs 39/204, 19%, p = 0.048). However, the relatively high proportions in both groups without detectable mumps neutralising antibody suggests the probable need for a second dose in order to achieve mumps elimination. No significant differences were found in the proportions with detectable antibody to measles between vaccines containing the Schwarz and the Enders-Edmonston strains. Overall, only 3% of vaccinees were without detectable measles antibody, although a further 28% had a level below 200 mille International Units, the putative protective level for clinical measles. Geometric mean titres (GMTs) to measles were twofold higher in girls vaccinated after than before 14 months of age; GMTs in boys were intermediate and showed no age effect. Over 99% of vaccinees were seropositive to rubella, confirming the excellent immunogenicity of the RA 27/3 rubella strain and the potential for elimination of rubella with a single dose strategy.

Immunogenicity of second dose measles-mumps-rubella (MMR) vaccine and implications for serosurveillance.

Measles and mumps, but not rubella, outbreaks have been reported amongst populations highly vaccinated with a single dose of measles-mumps-rubella (MMR) vaccine. Repeated experience has shown that a two-dose regime of measles vaccine is required to eliminate measles. This paper reports the effect of the first and second MMR doses on specific antibody levels in a variety of populations.2-4 years after receiving a first dose of MMR vaccine at age 12-18 months, it was found that a large proportion of pre-school children had measles (19.5%) and mumps (23.4%) IgG antibody below the putative level of protection. Only a small proportion (4.6%) had rubella antibody below the putative protective level. A total of 41% had negative or equivocal levels to one or more antigens. The proportion measles antibody negative (but not rubella or mumps) was significantly higher in children vaccinated at 12 months of age than at 13-17 months. There was no evidence for correlation of seropositivity to each antigen, other than that produced by a small excess of children (1%) negative to all three antigens. After a second dose of MMR, the proportion negative to one or more antigens dropped to <4%. Examination of national serosurveillance data, found that following an MR vaccine campaign in cohorts that previously received MMR, both measles and rubella antibody levels were initially boosted but declined to pre-vaccination levels within 3 years. Our study supports the policy of administering a second dose of MMR vaccine to all children. However, continued monitoring of long-term population protection will be required and this study suggests that in highly vaccinated populations, total measles (and rubella) IgG antibody levels may not be an accurate reflection of protection. Further studies including qualitative measures, such as avidity, in different populations are merited and may contribute to the understanding of MMR population protection.

Simultaneous IgM reactivity by EIA against more than one virus in measles, parvovirus B19 and rubella infection

BACKGROUND A clinical diagnosis of rash-causing infections is not always possible and reliance has to be placed on serological evidence of infection, especially on the presence of specific immunoglobulin (Ig)M. However, despite the use of modern serological methods and validated commercial kits, reports appear in the literature of simultaneous IgM reactivity against more than one virus in cases of Epstein Barr virus, rubella, cytomegalovirus, human parvovirus B19 (HPV B19) and measles infections, all with implications for the pregnant woman. OBJECTIVES We decided to evaluate the extent of the problem in rubella, measles and HPV B19 infections in a routine diagnostic laboratory. STUDY DESIGN We tested sera from cases with initial clinical and serological evidence of infection with measles, HPV B19 or rubella for evidence of simultaneous IgM reactivity against more than one virus. We confirmed primary infections with specific-IgG antibody avidity tests, and subjected sera with IgM reactivity against more than one virus to avidity tests to identify which, if any, of the three viruses was the cause of the primary infection. Groups of monoreactive IgM sera were randomly selected from the presented sera to demonstrate that the avidity of the IgG specific for the other two viruses would be of high avidity compared with the low avidity of the IgG specific for the virus against which specific IgM had been detected. RESULTS Our results confirm that simultaneous IgM reactivity against more than one virus does occur in these three infections, and that this is unlikely to be caused by the presence of rheumatoid factor. CONCLUSIONS In the absence of seroconversion, reliance on specific IgM results alone for diagnosis of these infections should be avoided and tests such as specific IgG antibody avidity should also be employed. The simultaneous occurrence of IgM reactivity against more than one virus is also important for epidemiological and surveillance reasons as the widespread use of the mumps, measles and rubella vaccine makes its impact on the population. Falsely diagnosed cases of apparent measles or rubella could throw into question the efficacy of the vaccine.

Seroprevalence of antibody to varicella zoster virus in England and Wales in children and young adults.

This is the first large-scale study to investigate the seroprevalence of varicella zoster (VZV) in the general population of England and Wales. The study focused on those aged 1-20 years, that age group in whom most infections occur. Prevalence rose rapidly with age, with 53% of children showing evidence of prior infection by the age of 5 years and most young adults having experienced infection. In addition to using a fixed cut-off recommended by the manufacturer, a mixture modelling technique was also used to define the proportion of the population seropositive in each age group. This was shown to be a more accurate approach to categorizing data from an epidemiological perspective.

The European Sero-Epidemiology Network: standardizing the enzyme immunoassay results for measles, mumps and rubella.

The ESEN (European Sero-Epidemiology Network) project was established to harmonize the seroepidemiology of five vaccine preventable infections including measles, mumps and rubella in eight European countries. This involved achieving comparability both in the assay results from testing in different centres and also sampling methodology. Standardization of enzyme immunoassay results was achieved through the development of common panels of sera by designated reference centres. The panels were tested at the reference laboratory and then distributed to each participating laboratory for testing using their routine methods. Standardization equations were calculated by regressing the quantitative results against those of the reference laboratory. Our study found large differences in unitage between participants, despite all using an EIA method standardized against an international or local standard. Moreover, our methodology adjusted for this difference. These standardization equations will be used to convert the results of main serosurvey testing into the reference country unitage to ensure inter-country comparability.

The seroepidemiology of measles in Western Europe

The European Regional Office of WHO has targeted measles for elimination from the region in 2007. Large national, age and sex stratified serological surveys of measles antibody were conducted in seven Western European countries from 1994-8 as part of the European Seroepidemiology Network. Three patterns were observed in the country-specific measles seroprofiles, ranging from (very) low susceptibility (four countries) to high susceptibility (one country). Susceptibility levels amongst 2-4-year-olds ranged from 2.9 to 29.8%, in 5-9-year-olds from 2.5 to 25% and 10-19-year-olds from 2.1% to 13.9%. A countrys susceptibility profile was highly associated with vaccine coverage for the first dose. First dose coverage ranged from 91 to 97.5% for low susceptibility countries, 75 to 85% for intermediate susceptibility countries and 55% for the high susceptibility country. Only the high susceptibility country still reports epidemic measles. In low susceptibility countries, which have achieved or are very close to measles elimination, the priority will be to maintain high MMR vaccine coverage in all geopolitical units for both vaccine doses. In moderate susceptibility countries there is still some endemic transmission, but also risk of outbreaks as pools of susceptibles accumulate. In the high susceptibility country the priority will be to increase infant vaccine coverage and reduce regional variation in coverage levels.